Composition and method of controlling fungi



3,077,433 Patented Feb. 12, 1963 This invention pertains to'novelorganic compounds and is particularly directed to novela-ethylisovalerate esters of 1-phenethyl-4-piperidinols in the form oftheir free bases and acid addition salts.

The compounds of the invention, in the form of their free bases, arerepresented by the following general structural formula:

wherein Y is selected from the group consisting of hydrogen, halogenhaving an atomic weight between 35 and 127, i.e., chlorine, bromine, andiodine, R and R wherein R is lower-alkyl, for example, methyl, ethyl,isopropyl, butyl, sec-butyl, amyl, isoamyl, hexyl, and like lower-alkylradicals.

The novel compounds of the invention are toxic to fungi, especiallyplant pathogenic fungi, and can be used to control the propagation offungi and hence, to prevent or eradicate fungal diseases of plants. Theyare effective, for example, against bean anthracnose (Colletotrichumlindemuthianum); they are also effective against bean rust (Uromycesphaseoli), early blight of tomatoes (Altermzria solani), and powderymildew of cucumbers (Erysiphe cichoracearum). The compounds of theinvention also possess analgetic activity. Further, the compounds of theinvention are useful, in accordance with US. Patents 1,915,334 and2,075,359, in forming amine fluosilicate mothproofing agents and, inaccordance with US. Patents 2,425,320 and 2,606,155, in formingaminethiocyanateformaldehyde condensation products for use as picklinginhibitors.

The fungicidally active l-phenethyll-piperidyl a-ethylisovalerates ofthis invention can be used in their pure state, but for practicalreasons it is preferred that they be used as fungicidal compositions.The compounds can be conveniently formulated as fungicidal compositionswith a diluent carrier and with or without adjuvants.

For example, fungicidal compositions useful against phytopathogenicfungi can be formulated with aqueous or nonaqueous carriers forapplication to foliage, seeds, or other parts of plants. Compositionssuitable for root or bole infusion can be made. Moreover, theactive'agents of the invention can be used alone in compositions, orthey can be used in combination with other fungicidal, virucidal,insecticidal, bactericidal or acaricidal agents.

It is usually desirable, particularly in the case of foliar sprayformulations, to include adjuvants such as wetting agents, spreadingagents, dispersing agents, stickers and adhesives, and the like, inaccordance with usual agricultural practices. Any of the conventionalwetting and dispersing agents of the anionic, cationic, and nonionictypes that are commonly employed in compositions for application toplants can be used. Surfactants having sutiicient wetting activity andtherefore suitable for the compositions of this invention include alkylsulfates and sulfonates, alkyl aryl sulfonates, sulfosuccinate esters,polyoxyethylene sulfates, polyoxyethylene-sorbitan monolaurate, al-

United States Patent Ofiice the surface tension of 7 per centimeter inconcentrations of about. 1%

an inert dusting powder, illustratively,

kyl aryl polyether sulfates, alkyl aryl polyether alcohols, alkylquaternary ammonium salts, sulfated fatty acid esters, sulfated fattyacid amides, glycerol mannitan laurate, polyalkylether condensates offatty acids, lignin sulfonates, and the like. It will be understood, ofcourse, that the sulfate and sulfonate compounds suggested above will beused in the form of their soluble salts, e.g., sodium salts. All ofthese surfactants are capable of reducing water to less than about dynesor less. Carriers suitable for diluting the active agents of theinvention include water, water containing a surfactant, or talc,pyrophillite, diatomite, clays such as bentonite, Georgia clay andAttapulgus clay, wood or walnut shell flour, and the like. The termdusting powder as used herein will be understood to refer to a solidmaterial comminuted to an average particle size less than microns,advantageously,

ylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile,cyclohexanone, or similar solvent. Such concentrated solutions can beadmixed with a suitable volume of an aqueous medium to give a mixture ofany desired concentration. For the most part, mixtures containing verylow concentrations of the active ingredient are effective.Illustratively, the concentration of the l-phenethyl- 4-piperidyla-ethylisovalerate can range from about 50 to 5000 ppm, depending uponthe amount of active material applied per acre. For example, excellentcontrol of powdery mildew on cucumbers, both protective and eradicative,has been obtained using concentrations of active ingredient ranging from125 to 2000' ppm. and without damage to the plants. For example, aconcentrate comprising 5% (by weight) of the compounddissolved in awater-miscible solvent of the kind noted above can be admixed with anaqueous medium in the proportions of one teaspoonful (about 5 cc.) ofconcentrate with one gallon of medium to give a mixture containing toparts of active ingredient per million parts of Water. Similarly, onepint of a 5% concentrate mixed with gals. of water provides about 60ppm. of active ingredient. In the same'manner, more concentratedsolutions of active ingredient in a water-miscible solvent can beincorporated with an appropriate quantity of aqueous medium to give amixture of desired concentration.

It will of course be appreciated that the conditions encountered Whenapplying the method and compositions of this invention to actualpractice can vary widely. included among the variables that may beencountered are the degree of infestation by pathogens, the particularplant being treated, the degree of development of the plant, theprevailing weather conditions, such as tempera; ture,=relative humidity,rainfall, dews, and so forth.

A suitable formulation is obtained by blending and milling 327 lbs. ofGeorgia clay, 4.5 lbs. of isooctylphenoxy polyethoxy ethanol (TritonX-l00) as a wetting agent, 9 lbs. of a polymerized sodium salt ofsubstituted benzoid long-chain sulfonic acid (Daxad 27) as a dispersingagent, and 113 lbs. of the active ingredient. The resulting formulationhas the following percentage composition (parts herein are by weightunless otherwise Polymerized sodium salt of. substitutedbehhbiddbhg:chain sulfonic acid 2 Georgia clay 72 .1-tetradecyl-4-methylpyridiniumchloride, Triton X-100 and Pluronic F-68 (ethylene oxide-propyleneglycol condensate, nonionic surfactant). If desired the surfactant canbe incorporated in the dry mixture either by dry milling or by adding itin solution in a volatile solvent such as ethanol or acetone, mixing toform a paste, drying, and milling.

The a-ethylisovalerate esters of the invention are readily obtained byesterifying a l-phenethyl-4-piperidinol having the following generalstructural formula:

wherein Y is as defined above, with a-ethylisovaleryl halide, forexample, a-ethylisovaleryl chloride, to produce a1-phenethyl-4-piperidyl a-ethylisovalerate having the Formula I.

Advantageously, the piperidinol compound and a-ethylisovaleryl halideare reacted in the presence of an inert solvent, illustratively ether,tetrahydrofuran, dioxane, toluene, xylene, benzene, and the like, and anacid acceptor, illustratively pyridine, lutidine, picoline,triethylamine, and the like. If desired, the acid acceptor can alsoserve as the inert solvent merely by employing a sufficient quantity ofthe same, without including an additional inert solvent of the kindillustrated. The reactants can be employed in stoichiometricproportions, i.e., equimolar proportions, or an excess of eitherreactant can be employed if so desired. Ordinarily, however, it ispreferred to employ the u-ethylisovaleryl halide in an amount which isat least equirnolar with respect to the piperidinol compound,particularly when an acid acceptor is included in the reaction mixture.The reaction proceeds satisfactorily at temperatures ranging from about25 to about 100C, particularly from about to about 75 C. After thereaction has been completed, the resulting 1-phenethyl-4-piperidyla-ethylisovalerate (Formula I, above) can be isolated in free base formin conventional manner, for example, by basifying the reaction mixture,illustratively with an aqueous solution of sodium hydroxide, extractingthe basic mixture with a solvent, illustratively ether, separating thelayers, and evaporating the organic layer. A

The acid addition salts of the free bases (Formula I above) are obtainedby neutralizing the free bases with acids, illustratively, hydrochloric,hydrobromic, sulfuric, phosphoric, sulfamic, acetic, lactic, tartaric,gluconic, citric, benzoic, salicylic, and like acids. For example, thefree base is dissolved in a solvent, illustratively, ethanol, and thedesired acid is added. The solvent is then evaporated, and the acidaddition salt formed by neutralization of the free base is thenpurified, if so desired, using conventional procedures such as recrystallization, etc.

The following examples are illustrative of the process and products ofthe present invention, but are not to be construed as limiting.

PREPARATION 1 Preparation of 1-Phenethyl-4-Piperidinol while maintainingthe temperature of the reaction mixture between 50 and 60 C., a solutionof 185.1 g. (1 mole) of phenethyl bromide in 500 ml. of ethanol wasadded. The reaction mixture was refluxed for 4 hours with stirring, andallowed to stand overnight at about 25 C. The mixture was then distilled(using a simple distilling head) until the head temperature reached C.,and it was then cooled to about 25 C. The mixture thus stripped ofethanol was then extracted with five ZOO-ml. portions of methylenechloride, and the combined methylene chlo ride extracts were washed withtwo -ml. portions of saturated sodium chloride solution. The washedmethyl ene chloride solution was then dried overnight with 50 g. ofanhydrous sodium sulfate. The solution was filtered, and concentrated todryness under reduced pressure. The last traces of solvent were removedby heating the residue at about 95 C. at about 40 mm. mercury pressurefor 20 minutes. The warm oily residue thus obtained was triturated withtwo 250-ml. portions of technical hexane (Skellysolve B). The trituratedresidue was dissolved in 100 ml. of absolute ethanol and the solutionwas warmed to 35 C.; 200 ml. of USP ether was then added while swirlingthe solution gently. The etherethanol solution was cooled slowly andrefrigerated at about 15 C. for 3 days, in order to induce crystallize.tion. The crystals were recovered on a filter, the filter cake waswashed with 50 ml. of cold ether, and the crystals of1-phenethyl-4-piperidinol were dried to constant weight in an oven at 50C. under reduced pressure; dry weight, 124.2 g., melting point,95.5-98.5 C. Following the procedure described above but substitutingfor phenethyl bromide the following: p-chlorophenethyl bromide,p-ethylphenethyl bromide, and p-methoxyphenethyl bromide;l-(p-chlorophenethyl)-4-piperidinol, l-(p-ethylphenethyl)-4-piperidinol,and l-(p-methoxyphenethyl)-4-piperidinol, respectively, were prepared.

PREPARATION 2 Preparation of u-Ethylz'sovaleryl Chloride ride wasrecovered as a liquid having a boiling point of 80 to 81.5 C. at 75 mm.of mercury pressure, a refractive index, 12 of 1.4276, and density, d of0.957.

EXAMPLE 1 Preparation of 1-Phenethyl-4-Piperidyl a-Ethylisovalerate andthe Hydrochloride Thereof A solution consisting of 4.46 g. (0.03 mole)of a-ethylisovaleryl chloride in 15 ml. of toluene was added dropwiseduring an interval of one hour to a stirring solution of 4.10 g. (0.02mole) of 1-phenethyl-4-piperidinol in 25 ml. of dry pyridine and 10 ml.of toluene at 0.5" C. The reaction mixture was stirred overnight at roomtemperature. It was then heated on a steam bath for 15 minutes, cooledto 5 C., and shaken with 50 ml. of icecold 5% aqueous sodium hydroxidesolution and 50 ml. of ether. After phase separation, the aqueous layerwas separated from the organic layer and extracted with two 50-ml.portions of ether. The ether extracts were combined with the organiclayer and the whole was washed with four 25-ml. portions of water. Theorganic solvents were then evaporated, leaving l-phenethyl-4-piperidylat ethylisovalerate as a red-brown oil.

The oil was dissolved in 25 ml. of absolute ethanol and 1.5 ml. ofconcentrated hydrochloric acid was added. The solution was concentratedto dryness, and the residue was triturated with several 25-ml. portionsof ether. The 1-phenethyl-4-piperidyl or-ethylisovalerate hydrochloridethus obtained, after two recrystallizations from water, melted at 264 to265 C.

Analysis.--Calculated for C H C1NO C, 67.87; H, 9.11; CI, 10.02; N,3.96. Found: C, 67.45; H, 9.11; Cl, 10.16; N, 3.92.

Following the procedure as described above but substituting hydrobromic,sulfuric, phosphoric, sulfamic, acetic, lactic, tartaric, gluconic,citric, benzoic, and salicylic acid for hydrochloric acid,1-phenethyl-4-piperidyl aethylisovalerate hydrobromide, sulfate,phosphate, sulfamate, acetate, lactate, tartrate, gluconate, citrate,benzoate, and salicylate, respectively, were prepared.

EXAMPLE 2 Preparation of I-(p-Ethylphenethyl)-4-Piperidyla-Ethylisovalerate and the Hydrochloride Thereof Following the procedureof Example 1, but substituting l-(p-ethylphenethyl)-4-piperidinol for1-phenethy1-4-piperidinol, l-(p-ethylphenethyl)-4-piperidyla-ethylisovalerate and the hydrochloride thereof were prepared.

EXAMPLE 3 Preparation of 1-(p-Il Iethoxyphenelhyl) -4-Piperidyl a-Ethylisovaierate and the Hydrochloride Thereof Following the procedureof Example 1, but substituting l-(p-methoxyphenethyl)-4-piperidinol for1-phenethyl-4- piperidinol, l-(p-methoxyphenethyl)-4-piperidylu-ethylisovalerate and the hydrochloride thereof were prepared.

EXAMPLE 4 Preparation of I-(p-Chlorophenethyl)-4-Piperidyl oc-Ethylisovalerate and the Hydrochloride Thereof wherein Y is selectedfrom the group consisting of hydrogen, halogen having an atomic weightbetween 35 and 127, and R and R wherein R is a lower-alkyl radical; and(2) acid addition salts thereof.

2. The method of controlling phytopathogenic fungi which comprisesapplying to plants a compound selected from the group consisting of: (1)compounds represented by the following structural formula wherein Y isselected from the group consisting of hydrogen, halogen having an atomicweight between 35 and 127, and R and R0 wherein R is a lower-alkylradical; and (2) acid addition salts thereof.

3. The method of protecting plants from damage caused by fungal diseasewhich comprises applying to the foliage of said plants an aqueous spraycontaining, as active ingredient, 1-phenethyl-4-piperidyla-ethylisovalerate hydrochloride.

4. Composition for the control of phytophathogenic fungi which comprisesa dispersible carrier, a surfactant, and, as active ingredient, acompound selected from the class consisting of: 1) compounds representedby the following structural formula wherein Y is selected from the groupconsisting of hydrogen, halogen having an atomic weight between 35 and127, and R and R0 wherein R is a lower-alkyl radical; and (2) acidaddition salts thereof.

5. Composition for the control of phytopathogenic fungi which comprises,as active ingredient, l-phenethyl- 4-piperidyl a-ethylisovalerate acidaddition salt dispersed in a carrier selected from the class consistingof a watermiscible solvent and surfactant, water and surfactant, adusting powder, and a water-dispersiblepowder.

6. Composition for the control of phytopathogenic fungi which comprises,as active ingredient, l-phenethyl- 4-piperidyl a-ethylisovaleratehydrochloride dispersed in water with surfactant.

References Cited in the file of this patent UNITED STATES PATENTS1,962,109 Alvord June 5, 1934 2,177,198 Goldsworthy Oct. 24, 19392,746,966 Biel May 22, 1956 2,816,895 Ehrhart et a1 Dec. 17, 19572,918,406 Biel Dec. 22, 1959 2,918,407 Biel Dec. 22, 1959 2,918,408 BielDec. 22, 1959 OTHER REFERENCES Amin et al.: J. Am. Pharm. Asso.,Scientific Edition, vol. 37, pages 243-245 (1948).

Loening et al.: J. Am. Chem. Soc, vol. 74, pages 3929-3931 (1952).

4. COMPOSITION FOR THE CONTROL OF PHYTOPHATHOGENIC FUNGI WHICH COMPRISESA DISPERSIBLE CARRIER, A SURFACTANT, AND, AS ACTIVE INGREDIENT, ACOMPOUND SELECTED FROM THE CLASS CONSISTING OF: (1) COMPOUNDSREPRESENTED BY THE FOLLOWING STRUCTURAL FORMULA